Adenoviruses cause 5-10% of respiratory illness in children and are associated with acute pneumonia in children in developing countries, where they are a major cause of illness and death. 5-15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50-80%. However, little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Identification of such host factors will enable better design of antiviral and immune suppressive therapy and adenovirus-based gene therapy. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease, because it can be studied in the natural host and there are inbred strains with different susceptibilities to MAV-1. The objective of this proposal is to define and characterize the host gene(s) underlying a major quantitative trait locus (QTL) for MAV-1 susceptibility in inbred mice. The central hypothesis is that the major QTL on Chromosome 15 for MAV-1 susceptibility in SJL/J mice contains an immune system gene that is polymorphic in susceptible and resistant mice. Genetic mapping will be combined with candidate gene approaches in two specific aims. (1) The major QTL for susceptibility will be fine mapped using several complementary approaches. A high density of polymorphic markers will be used to genotype recombinant progeny backcross, intercross, and third-generation cross mice (recombinant progeny testing). An interval-specific congenic strain will be constructed in which the interval from susceptible SJL/J mice will be introgressed into the resistant BALB/cJ background. Additional inbred mouse strains will be tested to determine whether they share a genetic basis for susceptibility with the major QTL in SJL/J mice. If so they will be used for fine mapping, haplotype analysis, and candidate gene identification. (2) A list of 20-30 candidate genes for the Chromosome 15 QTL will be compared for sequence and gene expression differences between susceptible and resistant strains. A candidate gene will be identified and tested genetically by replacing it in a resistant strain with the susceptible allele. The project is expected to identify a previously undescribed interaction between host immune response and viral immune evasion, thus increasing our understanding of viral infections and mechanisms of host response to pathogens. ? ? ?
